Method of determining absolute configuration of chiral compound

ABSTRACT

The absolute configuration of a chiral compound is determined by (i) coordinating the chiral compound to a metalloporphyrin having a carbon chain-crosslinked porphyrin dimer structure in which one of the two porphyrin rings has at least one ethyl or substituent bulkier than ethyl at at least one of the second peripheral carbon atoms from the carbon atom at the carbon chain crosslink site, and (ii) analyzing the resultant coordination compound by circular dichroism spectrophotometry to determine the absolute configuration of the asymmetric carbon based on the sign of the Cotton effect. The chiral compound has an asymmetric carbon bonded to a basic group capable of coordinating to the metal of the other porphyrin ring of the metalloporphyrin dimer or an asymmetric carbon atom adjacent to the carbon atom bonded to the basic group.

This application is the U.S. National Phase under 35 U.S.C. §371 ofInternational Application PCT/JP00/08559, filed Dec. 4, 2000, whichclaims priority to Japanese Patent Application No. 11/345538, filed Dec.3, 1999. The International Application was published under PCT Article21(2) in a language other than English.

TECHNICAL FIELD

The present invention relates to a method for determining the absoluteconfiguration of chiral compounds.

BACKGROUND ART

Conventionally, there have been attempts to determine the absoluteconfiguration of external ligands based on the induced Cotton effectsrevealed by the analysis of circular dichroism (CD) spectrophotometry.For example, the following are reported:

(1) E. Yashima, T. Matsushima, and Y. Okamoto (J. Am. Chem. Soc., 1997,119, 6345-6359) report on polymers forming a helical structure in thepresence of a chiral compound and describe that there is a goodcorrelation between the sign of the Cotton effect in the circulardichroism spectra induced by the ligand (chiral compound) and theabsolute configuration of the ligand.

However, since the helical structure is induced by the ion pair formedbetween the carboxylate group of the polymer side chain and the ammoniumgroup of the ligand, this method can be used for typical monoamines andaminoalcohols but is not applicable to alcohols.

(2) X. Huang, B. H. Rickmann, B. Borhan, N. Berova, and K. Nakanishi (J.Am. Chem. Soc., 1998, 120, 6185-6186) report on circular dichroisminduced in a long chain-crosslinked porphyrin diner by a chiral ligand.There is a correlation between the sign of the Cotton effect and theabsolute configuration of the ligand. In this system, however, circulardichroism is induced only when one ligand molecule is concurrentlycoordinated to two porphyrin units. Therefore, this method is usefulonly for bifunctional compounds such as diamines and aminoalcohols.

(3) M. Takeuchi, T. Imada, and S. Shinkai (Bull. Chem. Soc., Jpn., 1998,71, 1117-1123) report that a porphyrin dimer having a phenylboronic acidunit exhibits circular dichroism in the presence of a variety of sugars.

This method is applicable only to polyols (polyalcohols) which form achemical bond with boronic acid, and it is not a method for directlydetermining the absolute configuration around a specific asymmetriccenter.

(4) H. Tsukube, M. Hosokubo, M. Wada, S. Shinoda, and H. Tamiaki (J.Chem. Soc., Dalton Trans., 1999, 11-12) report that a tris(β-diketonato)lanthanide complex exhibits circular dichroism in the presence of chiralamino alcohols. In this system, however, monoamines or monoalcohols donot induce chirality.

(5) S. Zahn, and J. W. Canary (Org. Lett., 1999, 1, 861-864) report thatthe absolute configuration of amino acids and aminoalcohols can bedetermined based on the circular dichroism of their copper complexes.

However, this method is applicable only to bidentate amino acids andaminoalcohols and can not be used for monoamines or monoalcohols.

As is clear from the above, there have been no reports about a methodfor determining the absolute configuration of chiral compounds having awide variety of basic groups, such as monoalcohols.

The X-ray diffraction method is known as a method for determining theabsolute configuration of chiral compounds. However, there is alimitation in that this method is applicable only to crystallinecompounds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the circular dichroism of a zinc porphyrin dimer induced bya chiral amine.

FIG. 2 is a schematic diagram showing the mechanism of asymmetricinduction in a zinc porphyrin dimer.

FIG. 3 illustrates the moment directions of the maximum absorption bandof a porphyrin dimer.

FIG. 4 shows CD spectra obtained using (R)-(−)-1-cyclohexylethylamine inthe Example.

FIG. 5 shows CD spectra obtained using (R)-(−)-phenylethanol in theExample.

DISCLOSURE OF THE INVENTION

The principal object of the present invention is to overcome the limitsand problems of the prior art and provide a novel general-purpose methodfor precisely and easily determining the absolute configuration ofchiral compounds having a wide variety of basic groups.

The present invention provides the following methods for determining theabsolute configuration of chiral compounds:

1. A method for determining the absolute configuration of a chiralcompound which comprises:

-   -   coordinating the chiral compound to a metalloporphyrin, the        metalloporphyrin having a carbon chain-crosslinked porphyrin        dimer structure in which one of the two porphyrin rings has at        least one ethyl or substituent bulkier than ethyl at at least        one of the second peripheral carbon atoms from the carbon atom        at the carbon chain crosslink site,        the chiral compound having an asymmetric carbon bonded to a        basic group capable of coordinating to the metal of the other        porphyrin ring of the metalloporphyrin dimer or an asymmetric        carbon atom adjacent to the carbon atom bonded to the basic        group; and    -   analyzing the resultant coordination compound by circular        dichroism spectrophotometry to determine the absolute        configuration of the asymmetric carbon of the chiral compound        based on the sign of the Cotton effect.

2. The method according to item 1 wherein the ethyl or substituentbulkier than ethyl is 1) a hydrocarbon group having at least 2 carbonatoms, 2) an oxygen-containing substituent, 3) a nitrogen-containingsubstituent, 4) a halogen atom, or 5) a halogenated hydrocarbon group.

3. The method according to item 1 wherein the chiral compound is 1) aprimary amine, 2) a secondary amine, 3) a primary diamine, 4) asecondary diamine, 5) a monoalcohol, or 6) an aminoalcohol.

4. The method according to item 1 or 3 wherein the metalloporphyrin is acompound represented by the following formula (I):

{μ{{5,5′-(ethane-1,2-diyl)bis[2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphyrinato](4-)}-κN²¹,κN²², κN²³, κN²⁴, κN^(21′), κN^(22′), κN^(23′), κN^(24′)}}dizinc.

The present invention uses circular dichroism (CD) spectrophotometricanalysis as described above. In this analysis, the sign of the inducedCotton effect is determined by the absolute configuration of theasymmetric carbon of the external ligand. According to the CDexciton-chirality method (Harada, N.; Nakanishi, K.; Circular DichroicSpectroscopy-Exciton Coupling in Organic Stereochemistry; UniversityScience Books; Mill Valley, 1983., Nakanishi, K.; Berova, N. In CircularDichroism; Principles and Applications; Woody, R., Ed; VCH Publishers;New York, 1994; pp. 361-398), a clockwise orientation of two interactingelectronic transition moments produces positive chirality, while acounterclockwise orientation leads to negative chirality.

The present invention was accomplished based on the finding that thereis a specific correlation between the sign of the Cotton effect and theabsolute configuration of the asymmetric carbon of a chiral compound(R-isomer or S-isomer) as a ligand.

The basic principle of this determination of the absolute configurationis described below with reference to the case of zinc porphyrinrepresented by formula (I):

{μ{{5,5′-(ethane-1,2-diyl)bis[2,3,7,8,12,13,17,18-octaethyl-21H,23H-porphyrinato](4-)}-κN²¹,κN²², κN²³, κN²⁴, κN^(21′), κN^(22′), κN^(23′), κN^(24′)}}dizinc.

This zinc porphyrin has a porphyrin dimer structure in which one of theporphyrin rings has two ethyl groups (—CH₂CH₃) each bonded to the secondperipheral carbon atoms (b), (b) from the carbon atom (a) at thecrosslink site crosslinked by an ethylene chain (—CH₂—CH₂—).

Of course, in the present invention, it is also possible to use ametalloporphyrin which has, in place of the above ethylene chain, acarbon chain having a suitable number of carbon atoms (preferably, aC₂₋₃ carbon chain) such as an alkylene chain or the like, themetalloporphyrin ring having at least one bulky substituent in place ofat least one of the ethyl groups bonded to the porphyrin ring at thesites (b), (b).

The present inventors already found that a zinc octaethylporphyrin dimer(ZnD) as above undergoes a conformational change from syn to anti uponcoordination of an alcohol or an amine such as those represented by thefollowing formulas:

Further, the inventors newly found that upon coordination of a chiralalcohol or a chiral amine, asymmetry is induced in the anti conformer,whereby circular dichroism is exhibited as shown in FIG. 1. Themechanism of asymmetric induction is illustrated in FIG. 2. Thus it canbe understood that the porphyrins' orientation is twisted by the sterichindrance between the ethyl group (Et) of the porphyrin and the bulkiestsubstituent (X) bonded to the α carbon of the ligand, and the excitoninteraction between the porphyrin rings produces circular dichroism.

The correlation between the absolute configuration (R-isomer orS-isomer) of a ligand and the sign of the Cotton effect is demonstrated,for example, in Table 1. Table 1 indicates that there is acorrespondence between the sign of the Cotton effect and the stericconfiguration around the α carbon of amino or hydroxyl groups. As shownin FIG. 1, the peak occurring at a shorter wavelength shows the secondCotton effect, whereas the peak at a longer wavelength shows the firstCotton effect. The signs at the peaks may be positive or negative. Forexample, in the case of 1-phenylethylamine shown in FIG. 1, when theabsolute configuration is (R), the second Cotton effect is positive andthe first Cotton effect is negative. When the absolute configuration is(S), these signs are reversed. That is, when the first Cotton effect ispositive, the absolute configuration of the chiral compound is (S). Whenthe first Cotton effect is negative, the absolute configuration of thechiral compound is (R). Table 1 shows that this correspondence exists inmany chiral compounds. These results prove that the above assumptionabout the mechanism of chirality induction is correct. Based on thiscorrespondence, it is also possible to determine the absoluteconfiguration of chemical compounds whose absolute configuration isunknown.

TABLE 1 Assignment of absolute configuration of chiral amines andalcohols Second Absolute Cotton First cotton configuration (B_(⊥)(B_(II) Ligand and sign of ligand transition) transition) 2-Buthanol(R)-(−) + − (S)-(+) − + 1-Phenylethanol (R)-(+) + − (S)-(−) − +2-Buthylamine (R)-(−) + − (S)-(+) − + 1-Phenylethylamine (R)-(+) + −(S)-(−) − + 1-(1-Naphthyl)ethylamine (R)-(+) + − (S)-(−) − +1,2-Diaminocyclohexane (1R,2R)-(−) + − 1-Amino-2-propanol (R)-(−) + −(S)-(+) − + 2-Amino-4-methyl-1- (R)-(−) + − pentanol (S)-(+) − +1-Cyclohexylethylamine (R)-(−) + − (S)-(+) − + N-methyl-1 (R)-(+) + −phenylethylamine (S)-(−) − + 2-Methyl-1-butylamine (S)-(−) − +Bornylamine (1R,2S)-(+) − + 1,2-Diphenylethylene- (1R,2R)-(+) + −diamine (1S,2S)-(−) − +

In Table 1, the B_(II) transition is a transition occurring when themoments of two porphyrin rings are aligned in the direction of bondingthe porphyrin rings and the resulting absorption band is B-band. TheB_(⊥) transition is a transition occurring when the moments of twoporphyrin rings are in directions perpendicular to the direction ofbonding the porphyrin rings and the resulting absorption band is B-band(see the solid line in FIG. 3). In both the B_(II) transition and theB_(⊥) transition, the directions of moments of the two porphyrin ringsof a chiral porphyrin dimer are slightly misaligned with respect to eachother, as compared to the achiral porphyrin dimer (see the dotted linein FIG. 3).

As described above with respect to zinc porphyrin, the invention makesit possible to determine the absolute configuration of the asymmetriccarbon of chiral compounds.

The metalloporphyrin used in the method of the invention has acarbon-chain crosslinked porphyrin dimer structure in which one of thetwo porphyrin rings has ethyl or substituent bulkier than ethyl at atleast one of the second peripheral carbon atoms from the carbon atom atthe carbon chain crosslink site (i.e., the carbon atom bonded to thecrosslinking carbon chain, on one of the porphyrin rings).

The ethyl or substituent bulkier than ethyl means a substituent whosevolume is as large as or larger than ethyl. Examples of suchsubstituents include 1) hydrocarbon groups having at least 2 carbonatoms such as ethyl, propyl, butyl and the like, 2) oxygen-containingsubstituents such as ester groups (e.g., methyl ester, ethyl ester),carboxymethyl and the like, 3) nitrogen-containing substituents such asamino, amide, 2-aminoethyl and the like, 4) halogen atoms such as —Cl,Br—, —F and the like, and 5) halogenated hydrocarbon groups such aschloroethyl and the like. The same or different substituents may bebonded to a metalloporphyrin.

Any of a variety of metal porphyrin compounds can be used as themetalloporphyrin as long as the metal is a 6-coordinate metal. Suchmetals are not limited to zinc but also include Fe, Mn, Ru, etc. The twometals of the dimer may be the same or different.

The metalloporphyrin used in the present invention can be synthesized byknown methods (e.g., Japanese Unexamined Patent Publication No.255790/1999). The use of zinc porphyrin is especially preferred in thepresent invention.

The chiral compound whose absolute configuration can be determined bythe method of the invention is, basically, a compound having anasymmetric carbon bonded to a basic group capable of coordinating to themetal on the porphyrin ring of said metalloporphyrin dimer or anasymmetric carbon adjacent to the carbon atom bonded to said basic group(i.e., an asymmetric carbon bonded to the carbon atom having the basicgroup). In the metalloporphyrin dimer, one porphyrin ring has at leastone ethyl or substituent bulkier than ethyl and the other porphyrin ringbonded thereto has a metal.

Representative examples of such basic groups are amino and hydroxyl.More specifically, the chiral compound whose absolute configuration canbe determined by the method of the present invention is a compound whichforms a ligand for a metalloporphyrin. Representative examples of chiralcompounds are 1) primary amines, 2) secondary amines, 3) primarydiamines, 4) secondary diamines, 5) monoalcohols, and 6) aminoalcohols.

For example, all the compounds listed in Table 1 from 2-buthanol toN-methyl-1-phenylethylamine correspond to chiral compounds having anasymmetric carbon bonded to a basic group capable of coordinating to themetal of the porphyrin ring. 2-methyl-1-butylamine corresponds to achiral compound having an asymmetric carbon adjacent to the carbon atombonded to the coordinative basic group. With respect to compounds having2 or more asymmetric carbons such as bornylamine and diamine shown inTable 1, the absolute configuration of the asymmetric carbon bonded tothe amino group coordinated to the metal of the metalloporphyrin can bedetermined.

In the present invention, the chiral compound capable of forming aligand for a metalloporphyrin is coordinated to the metalloporphyrin,preferably in a non-ligand-forming solvent, and the resultingcoordination compound is analyzed by CD spectrophotometry.

That is, the new method of the present invention for determining theabsolute configuration of a variety of chiral compounds capable ofcoordination to metalloporphyrins comprises analyzing a mixed sample ofa chiral compound and a metalloporphyrin in a non-ligand solvent, bycircular dichroism (CD) spectrophotometry. According to this method, theabsolute configuration of chiral compounds can be directly observedwithout the need to derive any specifically modified compounds, and thechirality of the carbon atom directly bonded to the ligand-forming groupor a carbon atom adjacent to the carbon atom can be determined.

Representative examples of non-ligand solvents include halogenatedaliphatic hydrocarbons such as chloroform (CHCl₃), dichloride methane(CH₂Cl₂), dichloride ethane (CH₂ClCH₂Cl), tetrachloride ethane(CHCl₂CHCl₂), carbon tetrachloride (CCl₄) and the like, and aliphatichydrocarbons such as hexane, heptane and the like.

In the method of the present invention, samples to be analyzed by CDspectrophotometry can be prepared, for example, in the following manner:

A chiral compound and a metalloporphyrin are dissolved in said solvent.The concentrations of the chiral compound and the metalloporphyrin arenot critical. Generally, the concentration of the chiral compound shouldbe 10⁻⁴ mol/l or higher, and the concentration of the metalloporphyrin10⁻⁶ mol/l or higher. Their concentrations can suitably be selected fromthe above ranges in accordance with the type of solvent used, etc.

In the case of the metalloporphyrin of formula (1), the minimumconcentrations of chiral compounds required for observing sufficientCotton effects are as follows: primary acyclic monoamines preferablyhave a minimum concentration of about 10⁻³ mol/l, cyclic aromaticmonoamines about 10⁻⁴ mol/l, secondary amines about 10⁻⁴ mol/l, diaminesabout 10⁻³ mol/l and aminoalcohols about 10⁻³ mol/l. Preferably, theminimum concentration of monoalcohols required for observing sufficientCotton effects is about 10⁻¹ mol/l and the temperature is −80° C.

The following cases 1-5 can be mentioned as examples.

[Case 1]

The absolute chirality of primary monoamines can preferably bedetermined when the minimum concentration thereof in chloroform,dichloromethane, carbon tetrachloride, tetrachloroethane, hexane orheptane is adjusted to about 10⁻⁴ mol/l to 10⁻³ mol/l and theconcentration of the metalloporphyrin of formula (I) is about 10⁻⁶mol/l. Examples of primary monoamines include 2-butylamine,1-phenylethylamine, 1-(1-naphtyl)ethylamine, 1-cyclohexylethylamine,2-methyl-1-butylamine, and[endo-(1R)-1,7,7-trimethylbicyclo[2,2,1]heptan-2-amine].

[Case 2]

The absolute chirality of secondary monoamines can preferably bedetermined when the minimum concentration thereof in chloroform,dichloromethane, carbon tetrachloride, tetrachloroethane, hexane orheptane is adjusted to about 10⁻⁴ mol/l and the concentration of themetalloporphyrin of formula (I) is about 10⁻⁶ mol/l. Examples ofsecondary monoamines include N-methyl-1-phenylethylamine.

[Case 3]

The absolute chirality of diamines can preferably be determined when theminimum concentration thereof in chloroform, dichloromethane, carbontetrachloride, tetrachloroethane, hexane or heptane is adjusted to about10⁻³ mol/l and the concentration of the metalloporphyrin of formula (I)is about 10⁻⁶ mol/l. Examples of diamines include1,2-diphenylethylenediamine and 1,2-diaminocyclohexane.

[Case 4]

The absolute chirality of aminoalcohols can preferably be determinedwhen the minimum concentration thereof in chloroform, dichloromethane,carbon tetrachloride, tetrachloroethane, hexane or heptane is adjustedto about 10⁻³ mol/l and the concentration of the metalloporphyrin offormula (I) is about 10⁻⁶ mol/l. Examples of aminoalchols include1-amino-2-propanol and 2-amino-4-methyl-1-pentanol.

[Case 5]

The absolute chirality of monoalcohols can preferably be determined whenthe minimum concentration thereof is adjusted to about 10⁻¹ mol/l andthe concentration of the metalloporphyrin of formula (I) is about 10⁻⁶mol/l in dichloromethane or hexane at −80° C. Examples of monoalcoholsinclude 2-butanol and 1-phenylethanol.

The present invention enables precise and easy determination of theabsolute configuration of chiral compounds having a wide variety ofbasic groups bonded thereto. That is, the method of the invention canprecisely and easily determine the absolute configuration of the chiralcompounds having an asymmetric carbon directly bonded to a coordinativebasic group or an asymmetric carbon adjacent to the carbon atom bondedto the basic group. More specifically, the method of the presentinvention achieves the following excellent effects:

-   1) The absolute chirality of various optionally active compounds can    be directly observed.-   2) Only trace amounts of samples, i.e., metalloporphyrin (at the    level of μg) and chiral compounds (amines (μg), alcohols (mg)) are    needed.-   3) Since no chemical change occurs, the samples can be recovered    easily, if necessary.-   4) Determination of absolute chirality is very fast. Preparation of    the samples and measurement of the CD spectra can be done in 10    minutes.-   5) The detection of Cotton effects is usually carried out in the    region of 400 to 450 nm, while most chiral compounds have    absorptions up to 400 nm. Therefore, a wide variety of compounds can    be analyzed.-   6) The chiral compounds can be used without the need to derive any    specifically modified compounds.-   7) The absolute chirality of non-crystalline compounds can be    determined.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described below in further detail withreference to an Example.

EXAMPLE 1

A CH₂Cl₂ solution containing about 10⁻⁶ mol/l of zinc porphyrin offormula (I) and about 10⁻⁴ mol/l of (R)-(−)-1-cyclohexylamine wasprepared in a 3 ml cell, and the circular dichroism spectra wereobserved in the region of 350 nm to 500 nm at room temperature. FIG. 4shows the results.

The absolute configuration of a chiral compound is determined from thesign of the first Cotton effect at a longer wavelength. From thenegative sign of the first Cotton effect as shown in FIG. 4, theabsolute configuration of (R)-(−)-1-cyclohexylethylamine was confirmedto be (R).

Similarly, a CH₂Cl₂ solution containing about 10⁻⁶ mol/l of the zincporphyrin and about 10⁻¹ mol/l of (R)-(−)-1-phenylethanol was preparedin a 3 ml cell, and the circular dichroism spectra were observed in theregion of 350 nm to 500 nm at −80° C. FIG. 5 shows the results.

In this case also, the sign of the first Cotton effect was negative.Thus the absolute configuration of the chiral compound was confirmed tobe (R).

The method of the present invention determines the absoluteconfiguration of chiral compounds in the manner described above. Theeffectiveness of this method was also confirmed for the assignment ofthe absolute configuration of chiral amines and alcohols as shown inTable 1.

1. A method for determining the absolute configuration of a chiralcompound which comprises: coordinating the chiral compound to ametalloporphyrin represented by the following formula (I):

{μ{{5,5′- (ethane-1, 2-diyl) bis [2, 3, 7, 8, 12, 13, 17,18-octaethyl-21H, 23H-porphyrinato](4-)}-κN²¹, -κN²², -κN²³, -κN²⁴,-κN^(21′), -κN^(22′), -κN^(23′), -κN^(24′), }}dizinc, the chiralcompound having an asymmetric carbon bonded to a basic group capable ofcoordinating to the metal of the other porphyrin ring of themetalloporphyrin dimer or an asymmetric carbon atom adjacent to thecarbon atom bonded to the basic group; and analyzing the resultantcoordination compound by circular dichroism spectrophotometry todetermine the absolute configuration of the asymmetric carbon of thechiral compound based on the sign of the Cotton effect, wherein when thefirst Cotton effect is positive, the absolute configuration of thechiral compound is (S), and when the first Cotton effect is negative,the absolute configuration of the chiral compound is (R).
 2. The methodaccording to claim 1 wherein the chiral compound is 1) a primary amine,2) a secondary amine, 3) a primary diamine, 4) a secondary diamine, 5) amonoalcohal, or 6) an aminoalcohol.